1. Cystic fibrosis: From childhood to adulthood Eitan Kerem Department of Pediatrics and CF Center Hadassah University Hospital Jerusalem Israel

3. Vas deference

7. Ca 2+ Cl - cAMP Na + K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ 2Cl - Na + H2OH2O H2OH2O Cl - H2OH2O H2OH2O Na + Cl -

15. CFF Patient Registry Annual data report 2005

17. The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early diagnosis and prevention of non-apparent lung damage Early and aggressive antibiotic therapy of respiratory infection Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

19. Causes of malnutrition in CF Chronic lung diseasePancreatic insufficiency Malabsorption fat, micronutrient energy Increased losses Chronic cough Dyspnea Recurrent infections Increased needs Vomiting Fatigue Anorexia Decreased intake Malnutrition

20. The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early diagnosis and prevention of non-apparent lung damage Early and aggressive antibiotic therapy of respiratory infection Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

21. Physiotherapy Retained purulent secretions have etiologic role in airway disease Variety of techniques: –Postural drainage and percussion (CPPT) –Percussive vest –Airway maneuvers (PEP) –Flutter valves / airway occlusion devices (AOD) –Aerobic exercise

22. Physiotherapy routinely used: 1-3 times daily –Meta analysis 35 studies: PT better than no PT for clearance No long term evidence of therapeutic effect No evidence one technique superior to others

23. The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early diagnosis and prevention of non-apparent lung damage Early and aggressive antibiotic therapy of respiratory infection Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

24. Inhaled Hypertonic (7%) Saline Elkins et al. NEJM, 2006 354(3):229-40 7% inhaled BID following albuterol pretx x 48 wks 162 subjects, Age >6, with FEV 1 > 40% 70 mL increase in FEV1 (p>0.05), composite p<0.05

25. Dornase Alfa in Mild CF Quan JM, et al. J Pediatr, 2001 139(6):813-20 Dornase alfa Placebo Mean change from baseline 5 FEV 1 (% predicted) Treatment effect: 3.2% ± 1.2% predicted, *P = 0.006 * 70 75 80 85 90 95 100 01224364860728496 Week % Free of Exacerbation RR 0.66 [95% CI 0.44-1.00]; P < 0.05

26. The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early and aggressive antibiotic therapy of respiratory infection Early diagnosis and prevention of non-apparent lung damage Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

28. Chronic P aeruginosa colonization Predicts Poor Survival in CF Henry RL, et al. Pediatr Pulmonol, 1992; Mar;12(3):158-61. *P <0.01 mucoid vs no Pa or nonmucoid 0 20 40 60 80 100 0612182430364248 Months of observation % of patients without chronic infection Treatment (n = 48) Historical control (n = 43) Frederiksen B, et al. Pediatr Pulmonol, 1997; 23:330-335 P <0.005 treatment vs control

29. Avoid cross infection!!! Hand washing facilities and alcohol-based hand rubs must be present and used!

30. Patient segregation Fully indicatedFully indicated –B. cepaecia –MRSA Relatively indicated –P. aeruginosa

31. Antibiotic Therapy Guided by culture data –Sputum culture (for CF organisms) Recommended frequently (at every clinic visit) + with exacerbations Oral Therapy –Criteria: Mild exacerbation Sensitive organism – Treat 14-21 days Staph aureus: doxycycline, macrolide, amox/clavulanate… P aeruginosa: FQ +/- inhaled tobramycin or colistin

32. Inpatient Antibiotic Therapy IV Therapy –Criteria: Severe exacerbation Resistant bacteria Failed oral therapy –Treat 10-21 days 2 agents based on sputum culture data –RCT: PCN + Tobra vs. PCN + Placebo Decreased rate of readmission with Tobra –RCT: 3 rd agent offered no additional benefit –RCT: culture guided therapy of questionable benefit Multidrug resistance PSA: –Synergy studies available Smith AL; et al. Pediatr 1999 Aaron SD et al.Lancet 2005 Blumer JL et al. Chest. 2005

33. Ramsey et al. NEJM 340(1):23-30, 1999 Moss, R. B. Chest 2002;121:55-63 TOBI: Phase III 520 Patients randomized 300 mg BID nebulized 3 – 4 week tx periods +10 % vs. –2% change in FEV1 26% reduction in hospitalizations 2 year f/u trial: in adolescents showed similar results: 14.2% relative change in FEV1

34. Effect of Inhaled Tobramycin on Time to Exacerbation Time to first event (weeks) 01224364860728496 50 60 80 90 100 % of patients free of exacerbation 70 0 Tobramycin Phase III 2 Tobramycin - US Mild CF Study 1 P =.020 1 Murphy TD, et al. Pediatr Pulmonol. 38(4):314-20, 2004 2 Ramsey B, et al. NEJM 340(1):23-30, 1999

35. The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early and aggressive antibiotic therapy of respiratory infection Early diagnosis and prevention of non-apparent lung damage Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

36. Dissociation between structure and function Lung function FEV 1 - 99% FVC - 92% FEV 1 /FVC - 90% FEF 25-75 - 95% Boy 13 years

37. 10 yrs old, FEV1 – 86% FVC – 93% 13 yrs old, FEV1 – 96% FVC – 91% De Jong et al. ERJ 2004

38. The EarLy Inhaled Tobramycin for Eradication (ELITE) study Ratjen et al. Thorax 2010

39. Proportion of patients free of P. aeruginosa at day 28 and 1 month after the end of treatment Ratjen et al. Thorax 2010

40. Time to recurrence of P. aeruginosa Ratjen et al. Thorax 2010

41. The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early diagnosis and prevention of non-apparent lung damage Early and aggressive antibiotic therapy of respiratory infection Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

42. Anti-inflammatory Therapy: Glucocorticoids Systemic glucocorticoids Inhaled glucocorticoids Ibuprofen Azythromicin

43. Copyright restrictions may apply. Saiman et al. JAMA 2003;290:1749-1756. Mean Relative Change in FEV1 %Predicted

44. Copyright restrictions may apply. Proportion of Patients Remaining Exacerbation-Free Saiman, L. et al. JAMA 2003;290:1749-1756.

45. The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early diagnosis and prevention of non-apparent lung damage Early and aggressive antibiotic therapy of respiratory infection Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

46. Nielsen & Schiøtz Acta Paediatr Scand Suppl 1982 CF Cystic fibrosis in Denmark 1945-1981, evaluation of centralized treatment Cumulative survival rates in 283 CF patients

48. The German Cystic Fibrosis Quality Assessment project (CFQA) 1995 - 2006 < 18 yrs > 18 yrs < 50 patients N=57 >50 patients N=36

49. Routine clinic visits Spirometry tests Sputum cultures Antibiotic therapy The best CF centers had more:

50. The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early diagnosis and prevention of non-apparent lung damage Early and aggressive antibiotic therapy of respiratory infection Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

53. CFTR mutations vary in their frequency and distribution in different populations

54. 1/3608 in 2000 1/2714 in 1971-1987 Decreasing trend since the onset of genetic testing Cystic fibrosis birth rate in Canada Dupuiset et al., 2000

55. Number of new cases/year in the USA age of diagnosis < 1 year Provided by Bruce Marshall, NACFF

56. Unpublished results by Castellani….Assael 2009; Castellani, WS18 CF rate in North Italy - Veneto/Trentino 1994199619982000200220042006 1.5 2.0 2.5 3.0 3.5 4.0 Anno Incidenza x 10.000 A significant decrease, ~4/10,000 to ~1.5/10,000

57. Factors that led to the decrease in CF incidence 1. Carrier testing (pre-conception, prenatal diagnosis) and the option of pregnancy termination 2. Newborn screening resulting in decision of parents: Not to have other children Pre-implantation genetic diagnosis (PGD) Prenatal testing and pregnancy termination

58. Brittany (1990 to 2005) Scotet et al., J of Pediatr 2008 CF birth rate in Brittany, France

59. Culture - arranged marriage (prearranged marriage) BrideGroom ? ? CF birth rate among Ultra Orthodox Jews Preventing program - obligatory pre-arranged genetic testing

60. 1994-2008 201,614 individuals were screened 8,400 carries were identified, (4.4%) 312 potential couples with 1 - in - 4 risk Consequence None of these potential couples married. CF birth rate among Ultra Orthodox Jews No more CF births in this population since the initiation of the program Provided by Rabbi Ekstein, Dor Yeshorim

61. Therapeutic approaches based on “CFTR knowledge” a. Gene therapy b. Activation of non-CFTR chloride channels c. Mutation specific therapies Cloning of the CFTR gene - new era in CF research

62. Gene therapy - multidose trial Design 100 CF patients, 50 active v 50 placebo Age 12+ 12 months treatment (~ x1/month) Endpoints To be determent from the run-in study Duration Start: beginning of 2011 End – end of 2012 Eric Alton, UK;

63. Therapeutic approaches based on “CFTR knowledge” a. Gene therapy b. Activation of non-CFTR chloride channels c. Mutation specific therapies Cloning of the CFTR gene - new era in CF research

64. Identification of Ca 2+ - activated Cl - channels CFTR Cl - CaCC Cl - epithelial cell Ca 2+ -activated Cl - channels (CaCC) are present in the apical membrane of CF and non-CF epithelial cells. Activation of CaCC may compensate the deficit of Cl - transport in CF. Caputo et al., Science, 2008; Schroeder et al., Cell, 2008; Yang et al., Nature, 2008; Rock et al., 2009 Small molecules: Denufosol, Moli-1901

65. Therapeutic approaches based on “CFTR knowledge” a. Gene therapy b. Activation of non-CFTR Chloride channels c. Mutation specific therapies Cloning of the CFTR gene - new era in CF research

66. Classes of CFTR mutations R R Class II Protein processing R Cl - Class IV Impaired conductance R Cl - Class V Reduced level R Class III regulation X Class I No/low synthesis

71. Building a CF center in Gaza

73. Thank you!Thank you!